Central nervous system dysfunction is a common occurrence in systemic lupus erythematosus, and it is one of the serious life-threatening manifestations of the disease. Immune complex-mediated vasculitis, the mechanism responsible for tissue damage in most organ systems, is rarely found in the brain of patients with CNS disease. A major research effort in this laboratory has been the investigation of the role of antibodies reactive with neuronal cells from human brain in the pathogenesis of lupus neuropsychiatric manifestations. Our studies have demonstrated that most lupus patients have circulating antibodies reactive with human neurons, and many of those antibodies are cross-reactive with antigens on human lymphocytes. A pathogenetic role for those antibodies is suggested by the close association of antineuronal antibody within the central nervous system and active CNS lupus. In this application we are proposing more detailed analysis of the disease-producing potential of the neuron and lymphocyte reactive antibodies. Our aims are to understand how these antibodies get into the nervous system and to define the antigens with which they react. We will determine if the antibodies are produced locally within the central nervous system or if they enter from the serum through a leak in the blood-brain barrier. We will investigate their reactivity with the neurotransmitter receptors that regulate brain function, and we will utilize the neuron and lymphocyte reactive antibodies to physically characterize the antigens shared by those two cell types and analyze their distribution on lymphocyte subpopulations as a probe into the potential link between altered immune regulation and nervous system dysfunction that characterize SLE.